Thisproposalwilltestthehypothesisthatradiation-inducedlatelungandhearttoxicitiesareaconsequenceof endothelialdysfunctiondefinedasuncouplednitricoxidesynthetaseactivityanddecreasednitricoxide bioavailabilityestablishingastateofchronicinflammationdrivingapersistentpro-fibroticprocessassociated withabnormalwoundrepairandlatenormaltissueinjury.Forradiationasub-lethaldosethatinducesthe hematopoieticsyndrome(5Gy)immediatelyfollowedbythoraxonly?top-up?of6.5Gywillbeusedasthe radiationprotocol.Theproposalwilltestwhethersepiapterin,ametabolicprecursoroftetrahydrobiopterin,or inductionoftheinflammatoryprotein,hemeoxygenase-1,24hourspostIRre-establishesanormalwound repairmechanismremovingthedrivingforceforchronicinflammationandfibrosis.Theproposedexperiments alsotestwhetherexosomesshedfromirradiatedendothelialcellsprovidepotentialbiomarkersforthelate effectsofradiation.AIM1Hypothesis:radiationuncouplesnitricoxidesynthetaseactivitybyreducing tetrahydrobiopterinincardiacandlungendothelialcellsinvitroandthisresultsendothelialcelldysfunctionas evaluatedbymarkersofinflammation,senescenceandendothelial-mesenchymaltransition.AIM2 Hypothesis:oraladministrationofsepiapterinorinductionofhemeoxygenase-1expressionwithhemin24 hoursafteraradiationexposure,enhanceslungandcardiacfunctionasevidencedbydecreasedbreathing frequency,decreasedinflammation,enhancedcontractilereserve,improvedrelaxationanddiastolicfunction, reducedfibrosisandenhancedsurvival.AIM3Hypothesis:exosomesandtheircargopurifiedfromtheplasma ofirradiatedmiceinAim2andfromtheplasmaofpatientstreatedbyradiotherapyforlungandbreastcancer stimulateendothelialcelldysfunctionandrepresentapotentialsourceofbiomarkersforlungandcardiacinjury followingradiation.